Rare muscular dystrophies span a wide range of etiologies and symptoms but nearly all neuromuscular diseases are characterized by progressive muscle weakness that is unchecked by existing therapies. Myostatin inhibition is the target of a number of developing muscular dystrophy therapies. The clinical relevance of myostatin inhibition is based on documented increases in myostatin expression in dystrophic conditions and the increase in muscle size and strength when myostatin is reduced. Vector mediated myostatin blockage by follistatin overexpression is a viable treatment approach: follistatin is a potent myostatin antagonist and viral vector intramuscular delivery of follistatin results in enhanced muscle mass and performance in both normal and dystrophic tissue. Intramuscular gene delivery of follistatin may be a viable treatment strategy for some muscular dystrophies; however, intravascular delivery of follistatin may be necessary to address the systemic wasting associated with many neuromuscular conditions. Researchers at Nationwide Children's Hospital including Dr. Brian Kaspar and Dr. Jerry Mendell have made considerable advances in establishing proof of concept for follistatin gene delivery. Using a recombinant adeno-associated viral vector treatment approach, they have been able to establish the most efficient promoter system, vector serotype and optimize limb perfusion methods to achieve robust transgene expression in a safe and well tolerated manner. These results have been demonstrated in both rodents and non human primates. On the basis of these findings, a start- up company, Milo Biotechnology, was founded to commercialize the follistatin-based platform. A Phase I/II clinical trial to study the safety and efficacy of local intramuscular follistatin-AAV injections will begin in fall 2011. The regional intravascular approach proposed in this application will establish the safety and feasibility of rAAV-serotype8 follistatin gene therapy an facilitate follow-on IND-enabling studies. PUBLIC HEALTH RELEVANCE: Muscular dystrophies affect approximately 300,000 patients in the U.S.; a critical need exists to develop therapies that combat muscle wasting and increase quality of life. Proof-of-concept small and large animal studies in delivering follistatin locally ia adeno-associated virus (AAV) have been done at Nationwide Children's Hospital. This proposal seeks to build on that foundation, conducting initial experiments of a follistatin AAV therapy delivered regionally via the vasculature to treat systemic muscular dystrophies.